Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats

Abstract

Recurrent hypoglycemia is common in infants and children. In developing rat models, recurrent moderate hypoglycemia leads to neuronal injury in the medial prefrontal cortex. To understand the effects beyond neuronal injury, 3-week-old male rats were subjected to 5 episodes of moderate hypoglycemia (blood glucose concentration, approx. 30 mg/dl for 90 min) once daily from postnatal day 24 to 28. Neuronal injury was determined using Fluoro-Jade B histochemistry on postnatal day 29. The effects on brain-derived neurotrophic factor (BDNF) and its cognate receptor, tyrosine kinase receptor B (TrkB) expression, which is critical for prefrontal cortex development, were determined on postnatal day 29 and at adulthood. The effects on prefrontal cortex-mediated function were determined by assessing the prepulse inhibition of the acoustic startle reflex on postnatal day 29 and 2 weeks later, and by testing for fear-potentiated startle at adulthood. Recurrent hypoglycemia led to neuronal injury confined primarily to the medial prefrontal cortex. BDNF/TrkB expression in the prefrontal cortex was suppressed on postnatal day 29 and was accompanied by lower prepulse inhibition, suggesting impaired sensorimotor gating. Following the cessation of recurrent hypoglycemia, the prepulse inhibition had recovered at 2 weeks. BDNF/TrkB expression in the prefrontal cortex had normalized and fear-potentiated startle was intact at adulthood. Recurrent moderate hypoglycemia during development has significant adverse effects on the prefrontal cortex in the posthypoglycemic period.

Recurrent moderate hypoglycemia exacerbates oxidative damage and neuronal death leading to cognitive dysfunction after the hypoglycemic coma

“…It is well known that glucose reperfusion plays a major role in neuronal death, mainly when blood glucose exceeds physiological levels resulting in hyperglycemia. 40,50,51 Previous data have reported a decrease in GSH content even after a single episode of moderate hypoglycemia, 52 and some studies have shown that RH in healthy animals produces an increase in LPO and 4-HNE immunoreactivity, without leading to significant neuronal death or cognitive decline. 13,19,25 Furthermore, studies have reported that RH in healthy animals can even improve cognitive performance due to synaptic changes and brain metabolic adaptations.…”

Analysis of risk factors of neonatal hypoglycemia and its correlation with blood glucose control of gestational diabetes mellitus: A retrospective study

“…[ 2 ] Early manifestations of neonatal hypoglycemia may be asymptomatic or present as mild diaphoresis, lethargy, feeding difficulties, and decreased responsiveness, often lacking typical symptoms, thereby posing challenges for timely clinical detection. [ 3 ] Given that the energy supply to the neonatal brain primarily relies on glucose, persistent or recurrent episodes of hypoglycemia can profoundly disrupt neurological development, with severe cases even posing life-threatening risks. [ 4 ] Consequently, effective prevention and management of neonatal hypoglycemia hold paramount importance in ensuring healthy developmental outcomes for newborns.…”